title: Preclinical characterization of naturally occurring polyketide cyclophilin inhibitors from the sanglifehrin family.
abstract: Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F<4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2>5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.
authors.affiliation: Biotica Technology Ltd., Chesterford Research Park, Cambridge CB10 1XL, United Kingdom. matt.gregory@biotica.com
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Gregory
authors.forename: Michael
authors.initials: M
authors.lastname: Bobardt
authors.forename: Susan
authors.initials: S
authors.lastname: Obeid
authors.forename: Udayan
authors.initials: U
authors.lastname: Chatterji
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Coates
authors.forename: Teresa
authors.initials: T
authors.lastname: Foster
authors.forename: Philippe
authors.initials: P
authors.lastname: Gallay
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Mohammad
authors.initials: M
authors.lastname: Nur-e-Alam
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Mahmood
authors.initials: M
authors.lastname: Piraee
authors.forename: Dipen
authors.initials: D
authors.lastname: Suthar
authors.forename: Tony
authors.initials: T
authors.lastname: Warneck
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zhang
authors.forename: Barrie
authors.initials: B
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D004797:Enzyme-Linked Immunosorbent Assay; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007783:Lactones; D021983:Cyclophilins